Particular HLA class I associations with differential viral set-points and rates of progression to HIV disease provide potential insights into the mechanisms by which CD8+ T cells can influence outcome in HIV infection. Certain alleles are associated with effective control, whilst others are linked to rapid progression. The starting hypothesis underlying these proposed studies is that the diversity of these HLA-associated HIV outcomes may be primarily related to differences in the particular epitopes targeted, which in turn dictate the efficacy of the CD8+ T cell response. During the initial funding period of this grant, we focused our investigations in Durban, South Africa, in a region critically affected by the epidemic. We have identified the principal HLA class I alleles associated with low viral set-point, and those associated with high viral set-point; we have undertaken a comprehensive empirical analysis of the CD8+ T cell responses and have defined the majority of the epitopes that are characteristically targeted in this infected population. Initial studies of HLAB* 57 and B*5801, the two alleles most strong associated with low viral set-point in this cohort, indicated a likely contributory mechanism by which immune control may be brought about. The proposed studies expand on these findings and consider additionally the CD8+ T cell specificities that are associated with high viral set-point. A central hypothesis of this proposed work is that the goal of an HIV vaccine should not be to generate as many CD8+ T cell responses as possible, but rather to induce only certain efficacious CD8+ T cell specificities. Equally important, CD8+ T cell responses that have an actively deleterious influence on immune control need to be omitted from such a vaccine. The specific aims of the proposed studies are to a) define the epitopes that are targeted by the few alleles that are associated with extremes of outcome; b) identify which of these epitopes are associated with successful or unsuccessful control of viremia; and, c) to determine what is the likely evolutionary destiny, and therefore vaccine-relevance of these epitopes.